DESCRIPTION: HIV-associated neurocognitive disorders (HAND) affect 30-50% of HIV+ individuals, including those with virologic suppression on combination antiretroviral therapy (cART), and are disproportionately common in older individuals. Neurocognitive impairment in HIV is a source of disability not only in itself, but also because it magnifies impediments due to other HIV-associated non-AIDS (HANA) conditions by interfering with individuals' abilities to effectively implement personal and therapeutic compensatory strategies. Despite this, there is currently no effective treatment. Here we propose to address this need by combining a novel biomedical treatment, tesamorelin, and a state-of-the-art behavioral intervention, 2-way texting, to maximize adherence to study drug. Our preliminary data indicate that abdominal obesity (a marker of visceral adiposity), systemic inflammation, and immune activation are closely linked to HAND. The biomedical treatment will be a randomized, double-masked, placebo-controlled phase II clinical trial of tesamorelin (Tes), a GHRH analogue that reduces visceral adiposity, inflammation and immune activation. Tes has also been shown to increase IGF-1, which promotes brain angiogenesis, neurite outgrowth and synaptogenesis. Inclusion criteria will be HIV+, aged 40-70 years on stable cART for at least 12 weeks with undetectable viral load, with abdominal obesity and potentially reversible HAND. Exclusions will be individuals not meeting criteria for HAND based on published research diagnostic criteria (Antinori et al, 2007) as well as those with diabetes mellitus or hepatitis C coinfection. A total of 140 subjects will be enrolle at UCSD and USC and randomized 3:2 (tesamorelin:placebo) to achieve an evaluable sample of 106 subjects completing treatment for 9 months. We hypothesize that tesamorelin will improve the primary outcome of neurocognitive performance as measured by the global deficit score method. We will also evaluate secondary mechanistic outcomes as follows: 1) biomarkers of inflammation and monocyte activation, 2) brain magnetic resonance spectroscopy (MRS) evidence of cerebral inflammation and 3) MRI hippocampal volume increases. Multiple tools will be used to enhance adherence and combat treatment fatigue in this impaired population, including a state-of-the-art behavioral intervention comprising an adaptation of the individualized Texting for Adherence Building (iTAB) platform. Additional incentives to study participation will be provision of cell phones and data plans for text messaging, an open-label active study drug extension offered to all participants who complete the blinded placebo-controlled phase, and reimbursement for participant time and expense. By optimizing neurocognitive function, we endeavor to reduce the burden of disability in aging HIV-infected individuals on cART. Successful completion of this Phase II trial will lead to larger and longer duration Phase III studies to demonstrate efficacy.